Most biosensors and chemical sensors rely on specific molecular recognition events. See for example, G. Miller, W. C. Inkret, M. E. Schillaci, H. F. Martz, T. T. Little, Health Physics, Volume 78 (2000) 598; N. Iznaga, G. Nunez, J. Solozabal, A. Morales, E. Artaza, R. Rubio, E. Cardenas, Computer Methods and Programs in Biomedicine, Volume 47 (1995) 167; W. Gopel, Chemical imaging. 1. Concepts and visions for electronic and bioelectronics noises, sensors and actuators B, B52 (1998) 125; C. Nicolini, Thin solid films, Volume 284-285 (1996) 1; O. H. Willemsen, M. M. E. Snel, A. Cambi, J. Greve, B. G. Gooth, C. G. Figdor, Biophysical Journal, Volume 79 (2000) 3276 and M. Gomez-Lopez, J. A. Preece, J. F. Stoddart, Nanotechnology, Volume 7 (1996) 183. Specific molecular recognition events may be an antibody-antigen, DNA-DNA, or other ligand-receptor interactions. These recognition events are most commonly detected indirectly by various labeling techniques including radioactivity, enzymatic activity, visible markers, or fluorescent labels. See for example, M. Bras, J. Cloarec, F. Bessueille, E. Souteyrand, J. Martin, Journ. of Fluores., Vol. 10 (2000) 247. However, such techniques can be time consuming and often require relatively large, expensive instrumentation. Thus, there is a need for label free and continuous nanobiosensors for monitoring of bioaffinity interactions that can be easily integrated in array architecture on a CMOS chip. However, for most applications, arrays of currently available biosensors possess insufficient performance either due to large size, poor cross sensitivity, or long response times. Also, the majority of currently available biosensors are not compatible with complete CMOS Integration. Either the operation parameters of the biosensor are incompatible with CMOS, e.g. radioactive or fluorescence labeling, or the biosensor materials cannot be integrated within a CMOS process.
Recent efforts have focused on the development of cantilever-based sensors for the detection and transduction of chemical and biological processes. See for example, J. Fritz, M. K. Baller, H. P. Lang, H. Rothuizen, P. Vettiger, E. Meyer, H. J. Guntherodt, Ch. Gerber J. K. Gimzewski, Translating biomolecular recognition into nanomechanics, Science 288: 316-318 (2000); R. McKendry, J. Y. Zhang, Y. Amtz, T. Strunz, M. Hegner, H. P. Lang, M. K. Baller, U. Certa, E. Meyer, H. J. Guntherodt, C. Gerber, Multiple label-free biodetection and quantitive DNA-binding assays on a nanomechanical cantilever array, PNAS 99: 9783-9788 (2002); Y. Amtz, J. D. Seelig, H. P. Lang, J. Zhang, P. Hunziker, J. P. Ramseyer, E. Meyer, M. Hegner, C. Gerber, Label-free protein assay based on a nanomechanical cantilever array, Nanotechnology 14: 86-90 (2003); R. Berger, E. Delmarche, H. P. Lang, Ch. Gerber, J. K. Gimzewski, E. Meyer, H. J. Guntherodt, Surface stress I the self assembly of alkanethiols on gold, Science, Vol. 276 (1997) 2021; S. J. O'Shea, M. E. Welland, T. A. Brunt, A. Ramadan, T. Rayment, Atomic force microscopy stress sensors for studies in liquids, J. Vac. Si. Technol., Volume B14 (1996) 1383; M. Tortonese, R. C. Barrett, C. F. Quate, Atomic resolution with an atomic force microscope using piezoresistive detection, Appl. Phys. Letters, Volume 62 (1993) 834. Through various physical or chemical mechanisms, biological and chemical processes may induce nanomechanical motion in a microfabricated Si cantilever array. For example, asymmetric (one-side only) molecular adsorption induces incremental surface stress, which produces a nanoscale deflection in high-Q (>104) cantilever systems. Because of their low mass and high Q-factors, these miniaturized sensors show fast response times, high sensitivity, and are suitable for mass production using standard IC fabrication.
In order to monitor cantilever deflection, an optical detector is employed to detect the reflection of a laser off of the tip of the cantilever. This technique offers excellent sensitivity to molecular adsorption. Moreover, well-established techniques of surface functionalization (chemical and biomolecular) provide a contrast mechanism for molecule-specific adsorption. However, the required optical system to measure cantilever deflection limits application to 10 s or 100 s of cantilevers and reduces its applicability to large (1000 s to 10,000 s) arrays. Optical-based techniques also require a relatively large amount of power (i.e. a dedicated lasers/detectors) and are less able to be miniaturized.
An electronic detection method for biomolecules using symmetrical wheatstone bridge configuration (piezo-resistive detection) is described in A. Boisen, J. Thaysen, H. Jensenius and O. Hansen, Environmental sensors based on micromachined cantilevers with integrated read-out, Ultramicroscopy 82 (2000) 11-16. In this design a full wheatstone bridge was placed symmetrically on a chip. Two adjacent cantilevers comprise two of the bridge resistors. The second two resistors are placed on the substrate (via doping by Ion-implantation). This design enables differential measurements where the signals from the two cantilevers are subtracted. The relative resistance change of the piezo-resistor (ΔR/R) will be detected as an output voltage (Vo) from the wheatstone bridge with a supply voltage (V). The output voltage can be written as V0=¼V (ΔR/R). A differential amplifier will amplify the differential signal to improve the sensitivity of the cantilevers. Unfortunately, this detection method has a number of technological problems. One problem relates to non-linearities in the measurements. Another problem is serious low frequency noise. The cantilever bends by a few nanometers upon adsorption induced surface stress, so that even small noise issues cripple the validity of the measurements. A further problem is concerned with the difficulty of integration on a CMOS platform, which is required for miniaturization and on chip signal transmission and detection.
Utilizing combined electrical sensing and actuation of Si micro-cantilevers has been demonstrated in atomic force microscope imaging of materials such as graphite. See for example, S. Minne, G. Yaralioglu, S. Manalis, J. A. Adams, C. Quate, Appl. Phys. Lett., Vol. 72 (1998) 2340; S. C. Minne, S. R. Manalis, C. F. Quate, Integrated piezo-resistive and piezo-actuator based parallel scanning probe microscope, Appl. Phys. Letts., Volume 67 (1995) 3918. In this device, polysilicon-based piezo-resistors are put on a cantilever and an integrated piezo-actuator. This device suffers from thermal and electrical noise issues. Low frequency noise is a very critical parameter. Significant noise problems make feedback tracking unstable and can result in crashing of the cantilever with the surface of the material being imaged.